Summary of project + methods
This study is examining the association between DNA methylation and childhood eczema (up to ~10 years). Studies have data from different timepoints, so in the first instance we will classify individuals as ‘any eczema’ versus ‘no eczema’ according to all timepoints available up to age 10. Sub-analyses will be conducted that limits cases to those children who are diagnosed early in childhood (by ~2 years) or have persistent eczema (diagnosed by age 2 and have current eczema at age 8yrs).
The analyses will therefore use 3 binary definitions:
- Childhood AD - cases: AD by age 10, controls:no AD by age 10
- Early-onset AD - cases: AD by age 2, controls: no AD by age 2
- Persistent AD - cases: AD by age 2 and persisting to ~ 8-10yrs, controls: no AD by age 10
The association of each outcome with DNA methylation will be explored using logistic regression and 3 models with different covariates:
- model a: sex + batch (+ selection_factors) (+ ancestry)
- model b: sex + batch + maternal_age + maternal_smoking + maternal_SES + gestational_age (+selection_factors) (+ ancestry)
- model c: sex + batch + maternal_age + maternal_smoking + maternal_SES + gestational_age + cell_type (+ selection_factors) (+ ancestry)
See results of the meta-analyses using each AD definition and model below.
Childhood AD
Samplesizes
|
cohort
|
N
|
N_cases
|
N_controls
|
prevalence
|
|
ALSPAC
|
673
|
343
|
330
|
50.965825
|
|
CHS
|
197
|
50
|
147
|
25.380711
|
|
EDEN
|
153
|
69
|
84
|
45.098039
|
|
GENR
|
450
|
69
|
381
|
15.333333
|
|
INMA
|
462
|
216
|
246
|
46.753247
|
|
MoBa1
|
831
|
399
|
432
|
48.014440
|
|
MoBa2
|
418
|
179
|
239
|
42.822966
|
|
NEST_B
|
77
|
56
|
21
|
72.727273
|
|
NEST_W
|
41
|
22
|
19
|
53.658537
|
|
PREDO
|
792
|
54
|
738
|
6.818182
|
|
VITO
|
78
|
23
|
55
|
29.487179
|
|
GOYA
|
517
|
93
|
424
|
17.988395
|
|
IOW
|
616
|
179
|
437
|
29.058442
|
|
Total
|
5305
|
1752
|
3553
|
33.025448
|
QQ

manhattan

top hits
|
CpG
|
Gene
|
Chr
|
BP
|
Beta
|
SE
|
P
|
FDR_P
|
Direction
|
Isq
|
Het_p
|
|
model a
|
|
cg03030757
|
FANCE
|
6
|
35,420,754
|
-5.8e+00
|
1.206
|
1.7e-06
|
0.42
|
–+———-
|
0.0
|
7.4e-01
|
|
cg03738669
|
SLC4A11
|
20
|
3,218,476
|
-3.2e+00
|
0.674
|
2.6e-06
|
0.42
|
–+—-++-+–
|
30.9
|
1.4e-01
|
|
cg00888758
|
HRNR
|
1
|
152,196,674
|
-3.3e+00
|
0.713
|
2.9e-06
|
0.42
|
———-+–
|
0.0
|
9.1e-01
|
|
cg09768093
|
ZBTB8B
|
1
|
32,930,511
|
-1.9e+01
|
4.117
|
4.4e-06
|
0.47
|
——–+–+-
|
0.0
|
8.3e-01
|
|
cg03303325
|
TBCD
|
17
|
80,823,240
|
4.3e+00
|
0.983
|
1.1e-05
|
0.66
|
++++++++++–+
|
0.0
|
8.4e-01
|
|
cg09730123
|
SPSB3
|
16
|
1,827,948
|
-3.7e+00
|
0.856
|
1.4e-05
|
0.66
|
——–+-++-
|
0.0
|
4.5e-01
|
|
cg10142520
|
EHBP1L1
|
11
|
65,344,604
|
-3.1e+00
|
0.717
|
1.4e-05
|
0.66
|
———–+-
|
23.6
|
2.0e-01
|
|
cg00564723
|
CAMK2G
|
10
|
75,632,066
|
-4.5e+00
|
1.042
|
1.6e-05
|
0.66
|
–+—–+—-
|
0.0
|
8.5e-01
|
|
cg27021553
|
CCND1
|
11
|
69,462,783
|
-3.0e+00
|
0.705
|
2.1e-05
|
0.66
|
—–+—–+-
|
0.0
|
7.2e-01
|
|
cg14011244
|
|
11
|
130,240,665
|
-2.5e+00
|
0.588
|
2.2e-05
|
0.66
|
–++—–++–
|
28.3
|
1.6e-01
|
|
model b
|
|
cg19317715
|
AOC2
|
17
|
40,996,578
|
-2.8e+00
|
0.59
|
2.0e-06
|
0.32
|
———-+–
|
0.0
|
6.9e-01
|
|
cg03030757
|
FANCE
|
6
|
35,420,754
|
-5.9e+00
|
1.26
|
2.5e-06
|
0.32
|
–+———-
|
0.0
|
6.5e-01
|
|
cg00888758
|
HRNR
|
1
|
152,196,674
|
-3.4e+00
|
0.73
|
2.5e-06
|
0.32
|
——–+-+–
|
0.0
|
8.0e-01
|
|
cg09730123
|
SPSB3
|
16
|
1,827,948
|
-4.1e+00
|
0.88
|
3.0e-06
|
0.32
|
——–+-++-
|
0.0
|
4.6e-01
|
|
cg03303325
|
TBCD
|
17
|
80,823,240
|
4.6e+00
|
1.02
|
6.2e-06
|
0.51
|
++++++++++–+
|
0.0
|
7.1e-01
|
|
cg18028767
|
TSPAN4
|
11
|
859,873
|
-4.6e+00
|
1.02
|
7.7e-06
|
0.51
|
-+——–+-?
|
0.0
|
6.4e-01
|
|
cg03738669
|
SLC4A11
|
20
|
3,218,476
|
-3.1e+00
|
0.71
|
9.1e-06
|
0.51
|
–+—-++—-
|
30.9
|
1.4e-01
|
|
cg20762346
|
|
6
|
168,619,344
|
4.2e+00
|
0.96
|
1.2e-05
|
0.51
|
++++++++-+++?
|
0.0
|
6.1e-01
|
|
cg11772801
|
TMX1
|
14
|
51,711,237
|
-3.6e+00
|
0.82
|
1.2e-05
|
0.51
|
————-
|
0.0
|
5.5e-01
|
|
cg18560936
|
|
7
|
1,632,620
|
2.5e+00
|
0.58
|
1.2e-05
|
0.51
|
++++-++++++++
|
0.0
|
8.2e-01
|
|
model c
|
|
cg11772801
|
TMX1
|
14
|
51,711,237
|
-4.3e+00
|
0.93
|
4.3e-06
|
1
|
—+——–
|
11.4
|
3.3e-01
|
|
cg00888758
|
HRNR
|
1
|
152,196,674
|
-3.5e+00
|
0.80
|
1.0e-05
|
1
|
———+–
|
0.0
|
9.0e-01
|
|
cg04164048
|
IL34
|
16
|
70,680,498
|
5.6e+00
|
1.31
|
2.0e-05
|
1
|
+++++++-+-++
|
0.0
|
9.8e-01
|
|
cg03738669
|
SLC4A11
|
20
|
3,218,476
|
-3.1e+00
|
0.74
|
2.9e-05
|
1
|
–+–+-+—-
|
46.4
|
3.9e-02
|
|
cg19317715
|
AOC2
|
17
|
40,996,578
|
-2.7e+00
|
0.66
|
3.4e-05
|
1
|
–+——+–
|
0.0
|
6.3e-01
|
|
cg13917287
|
SLC15A1
|
13
|
99,401,109
|
-6.6e+00
|
1.58
|
3.4e-05
|
1
|
—-+–+—?
|
32.3
|
1.4e-01
|
|
cg21953146
|
MAPT
|
17
|
44,061,258
|
-4.0e+00
|
0.98
|
3.9e-05
|
1
|
—-+—?+–
|
0.0
|
6.7e-01
|
|
cg20330126
|
APOL5
|
22
|
36,125,053
|
-4.9e+00
|
1.20
|
4.5e-05
|
1
|
———-+-
|
23.0
|
2.2e-01
|
|
cg19668951
|
SLC39A13
|
11
|
47,430,812
|
-4.1e+00
|
1.02
|
5.1e-05
|
1
|
-+——–+-
|
0.0
|
7.3e-01
|
|
cg00564723
|
CAMK2G
|
10
|
75,632,066
|
-4.5e+00
|
1.11
|
5.4e-05
|
1
|
–+——+–
|
0.0
|
9.6e-01
|
Early-onset AD
Samplesizes
|
cohort
|
N
|
N_cases
|
N_controls
|
prevalence
|
|
ALSPAC
|
667
|
169
|
498
|
25.337331
|
|
CHS
|
197
|
41
|
156
|
20.812183
|
|
DCHS
|
266
|
26
|
240
|
9.774436
|
|
EDEN
|
142
|
48
|
94
|
33.802817
|
|
GENR
|
742
|
171
|
571
|
23.045822
|
|
INMA
|
348
|
83
|
265
|
23.850575
|
|
IOW-F2
|
171
|
28
|
143
|
16.374269
|
|
MoBa1
|
993
|
361
|
632
|
36.354481
|
|
MoBa2
|
386
|
210
|
176
|
54.404145
|
|
NEST_B
|
119
|
30
|
89
|
25.210084
|
|
UKIDS
|
607
|
216
|
390
|
35.584843
|
|
VITO
|
70
|
15
|
55
|
21.428571
|
|
GOYA
|
517
|
39
|
478
|
7.543520
|
|
IOW
|
667
|
99
|
569
|
14.842579
|
|
Total
|
5892
|
1536
|
4356
|
26.069246
|
QQ

manhattan

top hits
|
CpG
|
Gene
|
Chr
|
BP
|
Beta
|
SE
|
P
|
FDR_P
|
Direction
|
Isq
|
Het_p
|
|
model a
|
|
cg26014373
|
OLFML2A
|
9
|
127,572,640
|
8.8e+00
|
1.77
|
7.2e-07
|
0.26
|
+++++++++-+-+?
|
0.0
|
9.0e-01
|
|
cg19768607
|
|
11
|
68,768,879
|
1.0e+01
|
2.16
|
1.2e-06
|
0.26
|
+-++++++-++-++
|
2.1
|
4.3e-01
|
|
cg18372960
|
SDK1
|
7
|
4,305,728
|
-2.9e+00
|
0.62
|
2.3e-06
|
0.32
|
———+—-
|
0.0
|
8.5e-01
|
|
cg13863007
|
FGD3
|
9
|
95,766,607
|
-3.7e+00
|
0.81
|
5.0e-06
|
0.39
|
—–++——-
|
0.0
|
7.2e-01
|
|
cg00340921
|
PNPLA6
|
19
|
7,600,526
|
-1.1e+01
|
2.49
|
5.2e-06
|
0.39
|
–+-+——-+-
|
0.0
|
7.3e-01
|
|
cg14833040
|
|
6
|
47,197,781
|
8.8e+00
|
1.95
|
5.6e-06
|
0.39
|
+++++++++++-++
|
0.0
|
5.8e-01
|
|
cg00631837
|
PHF21B
|
22
|
45,404,212
|
-6.7e+00
|
1.51
|
1.0e-05
|
0.51
|
—-++—–++-
|
0.0
|
6.8e-01
|
|
cg10154010
|
ABCA3
|
16
|
2,326,080
|
7.8e+00
|
1.78
|
1.1e-05
|
0.51
|
++++++++-+++++
|
0.0
|
4.6e-01
|
|
cg24652615
|
TMEM151B
|
6
|
44,243,304
|
-1.3e+00
|
0.30
|
1.2e-05
|
0.51
|
-+——–+—
|
0.0
|
6.0e-01
|
|
cg26782881
|
MPP2
|
17
|
41,977,585
|
-5.1e+00
|
1.16
|
1.3e-05
|
0.51
|
———+—-
|
0.0
|
9.1e-01
|
|
model b
|
|
cg26014373
|
OLFML2A
|
9
|
127,572,640
|
8.9e+00
|
1.77
|
4.6e-07
|
0.20
|
+++++++++-+-+?
|
0.0
|
9.1e-01
|
|
cg19768607
|
|
11
|
68,768,879
|
1.1e+01
|
2.18
|
1.4e-06
|
0.30
|
+-++++++–+-++
|
0.0
|
4.6e-01
|
|
cg00340921
|
PNPLA6
|
19
|
7,600,526
|
-1.2e+01
|
2.52
|
5.1e-06
|
0.48
|
–+-+——-+-
|
0.0
|
7.9e-01
|
|
cg14833040
|
|
6
|
47,197,781
|
8.9e+00
|
1.96
|
5.1e-06
|
0.48
|
++++++++++++++
|
0.0
|
5.9e-01
|
|
cg18372960
|
SDK1
|
7
|
4,305,728
|
-2.8e+00
|
0.62
|
5.6e-06
|
0.48
|
—-+—-+—-
|
0.0
|
6.4e-01
|
|
cg10154010
|
ABCA3
|
16
|
2,326,080
|
7.9e+00
|
1.78
|
1.1e-05
|
0.59
|
++++++++++++++
|
0.0
|
4.7e-01
|
|
cg00447469
|
TFDP1
|
13
|
114,251,707
|
1.0e+01
|
2.30
|
1.1e-05
|
0.59
|
++++++-+-+++++
|
0.2
|
4.5e-01
|
|
cg00631837
|
PHF21B
|
22
|
45,404,212
|
-6.8e+00
|
1.54
|
1.1e-05
|
0.59
|
—-+——++-
|
0.0
|
8.1e-01
|
|
cg15275393
|
PARK2
|
6
|
162,067,688
|
-2.8e+00
|
0.66
|
1.5e-05
|
0.62
|
–?–++—-+–
|
0.0
|
8.8e-01
|
|
cg22063269
|
WBSCR16
|
7
|
74,489,892
|
1.0e+01
|
2.32
|
1.7e-05
|
0.62
|
++-+++?+-++-+-
|
11.1
|
3.3e-01
|
|
model c
|
|
cg26014373
|
OLFML2A
|
9
|
127,572,640
|
9.9e+00
|
1.92
|
2.5e-07
|
0.11
|
++–+++++++++?
|
0.0
|
9.4e-01
|
|
cg19768607
|
|
11
|
68,768,879
|
1.3e+01
|
2.56
|
5.5e-07
|
0.12
|
++++++++-++-++
|
0.0
|
8.5e-01
|
|
cg14833040
|
|
6
|
47,197,781
|
9.6e+00
|
2.10
|
5.1e-06
|
0.45
|
++-+++++++++++
|
0.0
|
7.6e-01
|
|
cg02872868
|
SORBS2
|
4
|
186,565,192
|
-3.5e+00
|
0.76
|
5.6e-06
|
0.45
|
—–++-+–+–
|
0.0
|
6.0e-01
|
|
cg18372960
|
SDK1
|
7
|
4,305,728
|
-3.0e+00
|
0.65
|
5.9e-06
|
0.45
|
—-+—-+—-
|
0.0
|
5.8e-01
|
|
cg19856241
|
|
4
|
148,233,162
|
8.3e+00
|
1.84
|
6.9e-06
|
0.45
|
+++++++++++–+
|
0.0
|
5.8e-01
|
|
cg27139419
|
IGF1R
|
15
|
99,212,404
|
-3.1e+00
|
0.68
|
7.5e-06
|
0.45
|
–+–+——-?
|
14.7
|
3.0e-01
|
|
cg24098008
|
|
10
|
132,877,018
|
-4.7e+00
|
1.08
|
1.4e-05
|
0.63
|
–?—?–+?+-?
|
0.0
|
7.0e-01
|
|
cg15275393
|
PARK2
|
6
|
162,067,688
|
-3.0e+00
|
0.70
|
1.5e-05
|
0.63
|
–?–++—-+–
|
0.0
|
8.4e-01
|
|
cg22063269
|
WBSCR16
|
7
|
74,489,892
|
1.1e+01
|
2.46
|
1.7e-05
|
0.63
|
++-+++?+-++-+-
|
14.0
|
3.0e-01
|
Persistent AD
Samplesizes
|
cohort
|
N
|
N_cases
|
N_controls
|
prevalence
|
|
ALSPAC
|
662
|
125
|
537
|
18.882175
|
|
CHS
|
197
|
35
|
162
|
17.766497
|
|
EDEN
|
126
|
18
|
108
|
14.285714
|
|
GENR
|
415
|
39
|
376
|
9.397590
|
|
MoBa1
|
519
|
87
|
432
|
16.763006
|
|
MoBa2
|
237
|
61
|
176
|
25.738397
|
|
VITO
|
66
|
11
|
55
|
16.666667
|
|
GOYA
|
517
|
33
|
484
|
6.382979
|
|
IOW
|
462
|
25
|
437
|
5.411255
|
|
Total
|
3201
|
434
|
2767
|
13.558263
|
QQ

manhattan

top hits
|
CpG
|
Gene
|
Chr
|
BP
|
Beta
|
SE
|
P
|
FDR_P
|
Direction
|
Isq
|
Het_p
|
|
model a
|
|
cg02716826
|
SUGT1P1
|
9
|
33,447,032
|
-6.6e+00
|
1.39
|
1.7e-06
|
0.39
|
–+——
|
0.0
|
9.0e-01
|
|
cg19322065
|
|
1
|
37,701,025
|
-3.7e+00
|
0.79
|
3.2e-06
|
0.39
|
———
|
0.0
|
9.8e-01
|
|
cg03723730
|
GRM4
|
6
|
34,031,694
|
-7.6e+00
|
1.63
|
3.3e-06
|
0.39
|
–+——
|
0.0
|
4.5e-01
|
|
cg10143807
|
EFNA3
|
1
|
155,050,924
|
1.4e+01
|
3.03
|
4.1e-06
|
0.39
|
++-++-+++
|
0.0
|
4.9e-01
|
|
cg20330126
|
APOL5
|
22
|
36,125,053
|
-7.4e+00
|
1.62
|
5.6e-06
|
0.39
|
——-+-
|
0.0
|
6.5e-01
|
|
cg24877842
|
TRAK1
|
3
|
42,201,898
|
-6.4e+00
|
1.42
|
6.1e-06
|
0.39
|
———
|
0.0
|
9.6e-01
|
|
cg11794356
|
OR6C3
|
12
|
55,725,991
|
-4.5e+00
|
1.00
|
7.2e-06
|
0.39
|
-+——-
|
0.0
|
8.4e-01
|
|
cg05233310
|
PRSS27
|
16
|
2,765,900
|
-7.6e+00
|
1.70
|
7.3e-06
|
0.39
|
-+——-
|
0.0
|
9.3e-01
|
|
cg00276389
|
TMPRSS6
|
22
|
37,466,935
|
-7.7e+00
|
1.79
|
1.4e-05
|
0.61
|
———
|
0.0
|
5.2e-01
|
|
cg02538891
|
|
9
|
139,549,426
|
-8.3e+00
|
1.91
|
1.4e-05
|
0.61
|
———
|
0.0
|
6.4e-01
|
|
model b
|
|
cg19322065
|
|
1
|
37,701,025
|
-3.7e+00
|
0.80
|
3.2e-06
|
0.49
|
———
|
0.0
|
9.7e-01
|
|
cg05233310
|
PRSS27
|
16
|
2,765,900
|
-8.0e+00
|
1.72
|
3.8e-06
|
0.49
|
-+——-
|
0.0
|
9.0e-01
|
|
cg03723730
|
GRM4
|
6
|
34,031,694
|
-7.7e+00
|
1.66
|
3.9e-06
|
0.49
|
–+——
|
0.0
|
6.0e-01
|
|
cg10143807
|
EFNA3
|
1
|
155,050,924
|
1.4e+01
|
3.14
|
5.6e-06
|
0.49
|
+++++-+++
|
0.0
|
5.8e-01
|
|
cg02716826
|
SUGT1P1
|
9
|
33,447,032
|
-6.5e+00
|
1.44
|
6.5e-06
|
0.49
|
–+——
|
0.0
|
6.7e-01
|
|
cg11794356
|
OR6C3
|
12
|
55,725,991
|
-4.5e+00
|
1.01
|
9.9e-06
|
0.49
|
-+——-
|
0.0
|
8.2e-01
|
|
cg24877842
|
TRAK1
|
3
|
42,201,898
|
-6.4e+00
|
1.46
|
9.9e-06
|
0.49
|
———
|
0.0
|
8.9e-01
|
|
cg14150666
|
CXCR2
|
2
|
218,991,310
|
-4.2e+00
|
0.96
|
1.1e-05
|
0.49
|
–+—+–
|
0.0
|
7.6e-01
|
|
cg00276389
|
TMPRSS6
|
22
|
37,466,935
|
-8.0e+00
|
1.82
|
1.1e-05
|
0.49
|
———
|
0.0
|
6.1e-01
|
|
cg27018461
|
PCCB
|
3
|
135,969,916
|
-7.5e+00
|
1.70
|
1.1e-05
|
0.49
|
—+–+–
|
39.7
|
1.0e-01
|
|
model c
|
|
cg05233310
|
PRSS27
|
16
|
2,765,900
|
-8.7e+00
|
1.81
|
1.6e-06
|
0.54
|
———
|
0.0
|
9.2e-01
|
|
cg19322065
|
|
1
|
37,701,025
|
-3.8e+00
|
0.83
|
4.2e-06
|
0.54
|
———
|
0.0
|
9.8e-01
|
|
cg20330126
|
APOL5
|
22
|
36,125,053
|
-8.7e+00
|
1.90
|
4.4e-06
|
0.54
|
——++-
|
43.4
|
7.9e-02
|
|
cg14150666
|
CXCR2
|
2
|
218,991,310
|
-5.0e+00
|
1.09
|
5.5e-06
|
0.54
|
–+—+–
|
0.0
|
7.9e-01
|
|
cg02716826
|
SUGT1P1
|
9
|
33,447,032
|
-7.4e+00
|
1.64
|
7.5e-06
|
0.54
|
–+—+–
|
0.0
|
5.1e-01
|
|
cg17504584
|
IQCC
|
1
|
32,671,645
|
-2.6e+01
|
5.82
|
8.3e-06
|
0.54
|
+——-?
|
0.0
|
6.7e-01
|
|
cg10143807
|
EFNA3
|
1
|
155,050,924
|
1.5e+01
|
3.36
|
9.0e-06
|
0.54
|
+++++-+++
|
19.6
|
2.7e-01
|
|
cg13280041
|
NHSL1
|
6
|
138,866,865
|
-5.0e+00
|
1.14
|
1.1e-05
|
0.58
|
——+–
|
0.0
|
9.1e-01
|
|
cg09903452
|
SEPT9
|
17
|
75,315,244
|
-7.8e+00
|
1.78
|
1.3e-05
|
0.61
|
–+—–+
|
27.5
|
2.0e-01
|
|
cg00276389
|
TMPRSS6
|
22
|
37,466,935
|
-8.2e+00
|
1.90
|
1.7e-05
|
0.62
|
———
|
0.0
|
4.6e-01
|
Correlation between models
